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The study was an inpatient, but PI left inpatient at MGH on July 1, 2012
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More than one out of three individuals treated for major depressive disorder (MDD) do not experience a full reduction of symptoms even when treated with adequate antidepressant medication. These individuals may have treatment-resistant depression. This is a condition that contributes to the tremendous costs of MDD, in terms of health care costs, functional impairment (limitation of an individual's functional ability), and diminished quality of life.
There is a clear need for personalized medicine, for people at high risk for treatment-resistant depression. If these individuals could be identified early in the course of their depression, they could be recommended for more intensive or specialized interventions. Doing so could improve their likelihood of having a full reduction in their symptoms.
Today, there are many treatment options for MDD. Individuals can spend months or years in and out of treatment before receiving one that works for their treatment-resistant depression.
The investigators want to study treatment resistant depression by examining specific genes (genotyping) that might influence how your body responds to certain antidepressant medications. This process of examining specific genes is not experimental. To look at your specific genes, the investigators will collect a blood sample. Genes contain the material passed from parent to child that determines the make-up of the body and mind. For example, some genes control the color of your hair or eyes. Genes are contained in your DNA (deoxyribonucleic acid). There are many differences in DNA, from one person to another. These differences may affect a person's chances of having a particular disease.
This will be a 6-month, randomized, controlled study of assay-guided treatment (AGT) versus treatment as usual (TAU) in adult inpatients with major depressive disorder. Two hundred subjects will be randomized to receive AGT or TAU. After subjects are screened, determined to be eligible, and complete baseline assessments, blood samples for genotyping will be obtained from all subjects as well as saliva samples for future GWAS analysis from all subjects. Only those subjects that are randomized to the AGT arm will have their blood samples immediately analyzed. Subjects in the TAU arm will have their blood samples stored for future analysis..
Once the blood samples are obtained, the attending psychiatrists will be asked to indicate their top three choices of antidepressants and at what doses they will initiate treatment. In order to prevent delays in providing treatments, the first choice antidepressants will be started prior to receiving assay results.
Upon receiving the assay reports (AGT arm), the attending psychiatrists will be asked whether the reports influenced their choice of antidepressant treatments and doses of antidepressants, as well as their confidence in their choices. The attending psychiatrists will then document any switches in antidepressant treatments or changes in doses of current antidepressant medications on a structured form. The assay reports will be available between 3 to 5 days after the blood samples are taken. The attending psychiatrists who are randomized to be provided the results of CYP genotyping will also be provided a phone number for consultation with Genomind Labs regarding the interpretation of the results.
Trough antidepressant blood samples for the AGT arm (10-12 hours after last dose) for therapeutic drug monitoring (TDM) will be obtained within 24 hours of discharge. Blood samples will also be obtained from the TAU arm, but they will be stored for future analysis of CYP genotyping and biomarker analysis of treatment resistant MDD. Clinical follow-up will proceed as felt to be clinically indicated. For subjects who have been discharged before the assay results are received, the attending psychiatrists will complete the from indicating changes in treatments as if patients were still in hospital. Results and recommendations will be forwarded to the identified outpatient psychiatrists. (note: blood levels of antidepressants were not analyzed)
The AGT arm is not standard care for patients with depression. The addition of assay-results and questionnaires makes the AGT arm different than standard care. Only the questionnaires make the TAU arm different than standard care.
Note:
Within 24 hours after you are admitted to the Inpatient Psychiatric Unit, the "baseline" assessment will occur. If you stay in the Inpatient Psychiatric Unit for more than one week, the "weekly" assessment will occur every 7 days. Typically, patients spend an average of 8-10 days in the Inpatient Psychiatric Unit. The day before or the day of your discharge from the Inpatient Psychiatric Unit, your "discharge" assessment will occur. One, 3, and 6 months after you are discharged, you will be asked to complete follow-up assessments.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment as Usual (TAU) | This group will provide blood samples to be analyzed at a later date for genotyping to determine the activity of CYP-450 enzymes that are important in metabolizing antidepressant medications.Treatment will be initiated based on the attending clinicians decision making absent genotyping results. All subjects in the group will receive the following assessment instruments for diagnosis: SCID-I/P and the Mini International Neuropsychiatric Interview (MINI) All subjects in the group will have the severity of their depression measured by the HAM D-17 (physician rating scale), the QIDS-SR-16 (patient rating). Clinical status will be measured by the CGI-S scale (1-7 with 7 being high functioning). Side effects ratings will be measured by the UKU. ATRQ will be used to assess the degree of treatment resistance by measuring the number of prior antidepressant trials. Patients in the TAU group will provide saliva samples for future GWAS analysis. | ||
| Assay Guided Treatment (AGT) | This group will provide blood samples for genotyping test to determine the activity of CYP-450 enzymes that are important in metabolizing antidepressant medications . This test result will be available within 3-5 days available to guide clinicians in their choice and dosing of antidepressant medications. All subjects in the group will have the severity of their depression measured by the Hamilton Depression Rating Scale-17 (physician rating scale), the QIDS-SR-16 (patient rating scale). Clinical status will be measured by the CGI-S scale (1-7 with 7 being high functioning). Side effects ratings will be measured by the Udvalg for Kliniske Undersogelser (UKU). ATRQ will be used to assess the degree of treatment resistance by measuring the number of prior antidepressant trials. Patients in the AGT group will provide saliva samples for future GWAS analysis. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Genotyping assays | Genetic | Patients will provide blood samples at the beginning of the study. If the patient is in the AGT group (as opposed to the TAU group), their blood samples will be sent for genotyping immediately. AGT psychiatrists will be given the results of genotyping within 3-5 days in order to decide which antidepressants to use long-term and at what doses. Patients in the Treatment as Usual group will have their blood samples stored for future analysis. Both groups will provide saliva samples for GWAS analysis at a alter date; however, since the study was terminated early, GWAS testing for both groups and genotyping for the TAU group were not performed. Patients will receive questionnaires to measure their mood, side effects, and symptoms. Patients will be asked to participate in 3 follow-up phone calls (1 month, 3 months, and 6 months) to measure their mood. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Quick Inventory of Depressive Symptoms-Self Rating (SR) 16 Item | To determine the efficacy of assay-guided treatment (AGT) versus treatment-as-usual (TAU), in terms of depression severity as measured by change in the Quick Inventory of Depressive Symptoms (QIDS-SR 16), adjusted for baseline severity, upon discharge, and at 1, 3, and 6 months post discharge from inpatient treatment. The QUIDS-SR 16 is a self rating 16 item multiple-choice questionnaire that measure severity of depression over the past week. The range on the QIDS-SR IS 0-27, with 0-5 indicating no depression; 6-10, mild depression; 11-15; moderate depression; 16-20 severe depression; and greater than or equal to 21, very severe depression. | Measured: Baseline (within 72 hours of admission), once weekly (+/- 24 hours), discharge (7-10 days after admission +/- 24 hours), and 1, 3, 6 months after discharge (+/- 4 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| Clinician's Report That AGT Modified His/Her Decision Regarding Which Antidepressant to Prescribe. | Clinicians randomized to receive AGT results were asked to report whether the AGT results impacted their decision making with regards to their choice of antidepressant and/or dosing of the antidepressant. | Measured: +/- 24 hours of baseline assessments and +/- 24 hours of receiving assay results |
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Inclusion Criteria:
Exclusion Criteria:
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The study was conducted on the 24-bed inpatient psychiatric unit at Massachusetts General Hospital. Written informed consent was obtained using the MGH-IRB approved consent form. A competency assessment consisting of four questions about the study was obtained. All subjects received a comprehensive psychiatric and medical evaluation including a comprehensive metabolic panel, TSH B12, folic acid, lipid panel and a urine pregnancy test for women of child-bearing age. Subjects needed to meet DSM-IV criteria for major depressive disorder.
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| Name | Affiliation | Role |
|---|---|---|
| John D Matthews, MD | Massachusetts General Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Massachusetts General Hospital | Boston | Massachusetts | 02114 | United States |
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Although clinicians were randomized to either receive or not receive the AGT results, they were not considered enrolled. Only the patients were enrolled in the study. Also, each participating clinician covered only one subject.
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment as Usual | Subjects will provide blood samples prior to treatment, but will have their blood stored for later analysis. Subjects will receive questionnaires to measure their mood, side effects, and symptoms. Subjects will provide a saliva samples for GWAS analyses at a later date. However, the GWAS analyses were not performed due to the early termination of the study. |
| FG001 | Assay Guided Treatment | This test is used to guide clinicians in their recommendation antidepressant drugs based on CYP 450 gene activity for 1A2, 2C9, 2C19, 2D6, and 3A/4. Subjects will be asked to provide blood samples. For subjects in the Assay-Guided Treatment group, their blood will be genotyped. Their psychiatrists will be given the results of the tests and then they will decide which antidepressants to use. Subjects will receive questionnaires to measure their mood, side effects, and symptoms. Subjects will be asked to provide saliva samples for GWAS analysis at a later date; however, GWAS analysis was not performed due to early termination of the study. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Treatment as Usual | Subjects in the Treatment as Usual group will proceed with treatment as usual, but have their blood samples for genotyping stored for future analysis. Patients will receive questionnaires to measure their mood, side effects, and symptoms. Subjects will be asked to provide saliva samples for GWAS analysis at a later date (note: GWAS analysis and genotyping for the Treatment as Usual group was not performed due to early termination of the study) Patients will be asked to participate in 3 follow-up phone calls to measure their mood. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Quick Inventory of Depressive Symptoms-Self Rating (SR) 16 Item | To determine the efficacy of assay-guided treatment (AGT) versus treatment-as-usual (TAU), in terms of depression severity as measured by change in the Quick Inventory of Depressive Symptoms (QIDS-SR 16), adjusted for baseline severity, upon discharge, and at 1, 3, and 6 months post discharge from inpatient treatment. The QUIDS-SR 16 is a self rating 16 item multiple-choice questionnaire that measure severity of depression over the past week. The range on the QIDS-SR IS 0-27, with 0-5 indicating no depression; 6-10, mild depression; 11-15; moderate depression; 16-20 severe depression; and greater than or equal to 21, very severe depression. | Quick Inventory of Depression symptom-16 (QIDS-SR 16) Baseline. Data was not collected for all time points for all participants. | Posted | Mean | Full Range | Score on QIDS-SR | Measured: Baseline (within 72 hours of admission), once weekly (+/- 24 hours), discharge (7-10 days after admission +/- 24 hours), and 1, 3, 6 months after discharge (+/- 4 weeks) |
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Six months for one subject in the TAU group. Up to 2 weeks for two AGT subjects and one TAU subject. These subjects did not complete 1 month, 3 month, or 6 month follow up visits due to lost to follow up and early termination of the study.
There were no all cause mortality or serious adverse events. All adverse events were expected and measured using the Udvalg for Kliniske Undersogelser (UKU).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Treatment as Usual (TAU) | Patients in the TAU group provided blood samples to obtain genotyping to determine the specific activity of genes important in metabolizing antidepressants and to be processed at a later date; however, these blood samples were not analyzed due to the early termination of the study. Patients received questionnaires to measure their mood, side effects, and symptoms. Patients provided a saliva sample for GWAS analysis at a later date; however, GWAS analysis was not done due to the early termination of the study. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John D. Matthews, M.D., M.Sc. | Massachusetts General Hospital, Boston, MA | 617-643-9095 | jmatthews@partners.org |
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| ID | Term |
|---|---|
| D061218 | Depressive Disorder, Treatment-Resistant |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
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Although the protocol included taking saliva samples from all subjects for GWAS analysis at a later date, GWAS analysis was not performed on any of the subjects due to the early termination of the study..
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| Treatment Adherence | To determine the impact on adherence of AGT versus TAU at 7-10 days after admission | To determine the impact on adherence of AGT versus TAU at 7-10 days after admission |
| Adverse Events (Side Effects) | To determine the impact of AGT versus TAU on total number of side effects determined by using the Udvalg for Kliniske Undersogelser (UKU).
| Measures at discharge, 1 month, 3 months, and 6 months |
| BG001 | Assay Guided Treatment | This group will receive a genotyping test to determine the specific levels of gene activity. This test was used to guide clinicians decision making for which antidepressants to prescribe and/or at what doses. Subjects will receive questionnaires to measure their mood, side effects, and symptoms. Subjects will be asked to provide saliva samples for GWAS analysis at a later date (note; GWAS analysis was not performed in the AGT group due to early termination of the study. Subjects will be asked to participate in 3 follow-up phone calls to measure their mood. |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Age, Continuous | Mean | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| OG000 |
| Treatment as Usual |
Subjects will be asked to provide blood samples for CYP 450 genotyping; however, the genotyping analysis will occur at a later date. Subjects will receive questionnaires to measure their mood, side effects, and symptoms. Subjects will be asked to provide a saliva sample for GWAS analysis at a later date. (note: genotyping analysis and GWAS analysis was not performed due to early termination of the study) |
| OG001 | Assay Guided Treatment | This test is used to guide clinicians in their recommendations for antidepressant drugs based on CYP 450 gene activity for 1A2, 2C9, 2C19, 2D6, and 3A/4. Subjects will be asked to provide a blood samples for CYP 450 genotyping. Subjects in the Assay-Guided Treatment group, will have their blood samples genotyped immediately. Their psychiatrists will be given the results of the tests within 3 to 5 days and then they will decide which antidepressants to use. Subjects will receive questionnaires to measure their mood, side effects, and symptoms. Subjects will be asked to provide a saliva sample for GWAS analysis at a later date. (note: GWAS analysis was not performed due to early termination of the study) |
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| Secondary | Clinician's Report That AGT Modified His/Her Decision Regarding Which Antidepressant to Prescribe. | Clinicians randomized to receive AGT results were asked to report whether the AGT results impacted their decision making with regards to their choice of antidepressant and/or dosing of the antidepressant. | 2 of 4 clinicians received AGT results for antidepressant decision making. One of two clinicians randomized to receive AGT results reported that his choice of antidepressant was definitely influenced by AGT results; the other clinician randomized to receive AGT results did not receive the AGT information within the defined time limit. | Posted | Number | participants | Measured: +/- 24 hours of baseline assessments and +/- 24 hours of receiving assay results |
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| Secondary | Treatment Adherence | To determine the impact on adherence of AGT versus TAU at 7-10 days after admission | Number of subjects adherent to antidepressant medications | Posted | Count of Participants | Participants | To determine the impact on adherence of AGT versus TAU at 7-10 days after admission |
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| Secondary | Adverse Events (Side Effects) | To determine the impact of AGT versus TAU on total number of side effects determined by using the Udvalg for Kliniske Undersogelser (UKU).
| Missing data on one AGT subjects | Posted | Number | Number of side effects | Measures at discharge, 1 month, 3 months, and 6 months |
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| 0 |
| 2 |
| 0 |
| 2 |
| 2 |
| 2 |
| EG001 | Assay Guided Treatment (AGT) | Patients in the AGT provided blood samples to obtain genotyping to determine the specific activities of genes important in metabolizing antidepressants. This test was used, at the beginning of treatment to guide clinicians in making recommendations as to which antidepressants and at what doses to prescribe. Patients received questionnaires to measure their mood, side effects, and symptoms. Patients in the AGT group provided saliva samples for GWAS analysis; however, GWAS analysis was not done due to the early termination of the study. | 0 | 2 | 0 | 2 | 1 | 2 |
| Sedation | Nervous system disorders | Systematic Assessment |
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| Reduced sexual desire | General disorders | Systematic Assessment |
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| Increased dreaming | Psychiatric disorders | Systematic Assessment |
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| Dry mouth | Gastrointestinal disorders | Systematic Assessment |
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| weight gain | Gastrointestinal disorders | Systematic Assessment |
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| Increased appetite | Gastrointestinal disorders | Systematic Assessment |
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| Increased sleep | Psychiatric disorders | Systematic Assessment |
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| Dystonia | Nervous system disorders | Systematic Assessment |
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| AGT not beneficial in decision making |
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| Number adherent at 1 month |
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| Number adherent at 3 months |
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| Number adherent at 6 months |
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| Number of side effects at 1 month |
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| Number of side effects at 3 months |
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| Number of side effects at 6 months |
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